ANTICIPATION OF AUTOSOMAL-DOMINANT PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA WITH HYPOGONADISM

A large Swedish family with members affected by progressive external o phthalmoplegia with hypogonadism were followed-up and reviewed, Hypogo nadism included delayed sexual maturation, primary amenorrhea, early m enopause, and testicular atrophy. Cataracts, cerebellar ataxia, neurop athy, hypoacusia, pes cavus, tremor, parkinsonism, depression, and men tal retardation were other features observed in this family, Muscle bi opsy samples of advanced cases showed ragged-red fibers, focal cytochr ome c oxidase deficiency, and multiple mtDNA deletions by Southern blo t analysis. An autosomal dominant mode of inheritance was evident with anticipation in successive generations. Linkage analysis excluded the chromosome 10q23.3-q24.3 region reported as being linked to the disea se in a Finnish family with autosomal dominant progressive external op hthalmoplegia. We report for the first time clinical evidence for anti cipation in a family with autosomal dominant progressive external opht halmoplegia. We hypothesize that the nuclear gene causing this enigmat ic disorder may be directly influenced by an expansion of an unstable DNA sequence and that the resulting phenotype is caused by a concerted action with multiple deletions of mtDNA. (C) 1996 John Wiley & Sons, Inc.